To maintain their stability, injectable preparations of a peptide, e.g., growth hormone, are provided in two-component forms consisting of a dried pharmaceutical component prepared by lyophilization, for example, and a liquid pharmaceutical component (a solvent liquid such as a buffered solution) in which the former component is dissolved to give an injectable liquid. And, to allow easy and reliable handling by patients, two-compartment syringes (also called dual-chamber cylinder ampoules) are widely employed for, e.g., human growth hormone preparations, in which those two components are contained in a single syringe separately from each other (see FIG. 1).
A two-compartment syringe, as shown in FIG. 1 as a side cross-sectional view, leftward direction of which represents the upward direction, is partitioned in its interior with two slidable walls in a liquid tight fashion (slidable front wall 2 and slidable rear wall 3) to enclose a front space 4 and a rear space 5. In the front space 4 and slightly forward of the slidable front wall 2, an elongated longitudinal groove 6 is defined in the inner wall of the two-compartment syringe, which groove has a length enough to stride the thickness of the slidable front wall 2 (therefore being a little longer than the thickness of the slidable front wall 2), so that a bypass through the groove may be created when the whole body of the slidable front wall 2 is placed within the range of the groove 6. In the front space 4 is enclosed a dried pharmaceutical component 10 such as a lyophilized powder, and in the rear space 5 a solvent liquid 11 used to dissolve the dried pharmaceutical component. At the front end of the two-compartment syringe 1, a septum 13 which can be pierced by a double-ended needle is fit in a fluid tight fashion and secured there with a cap 15 from outside.
Mixing of the dried pharmaceutical component 10 and the solvent liquid 11 is performed within the two-compartment syringe as follows: referring to FIG. 2, the syringe is held with its front end facing upward, and then a double-ended needle 18 is fixed as shown piercing through the septum 13 at the front end. The lumen of the double-ended needle thus communicates the front space 4 with the outside of the syringe. Then, the head 21 of the piston rod 20 of the injection device is put on the back of the slidable rear wall 3. As the piston rod 20 is pushed in, the liquid pharmaceutical component in the rear space 5 (and also air if present) and the slidable front wall 2 also are pushed in together with the slidable rear wall 3. Referring to FIG. 3, when rear end of the groove 6 is exposed at the rear edge of the slidable front wall 2, a bypass is formed through the groove 6 between the front space 4 and the rear space 5, through which bypass the solvent liquid 11 contained in the rear space 5 begins to be transferred into the front space 4, whereas the slidable front wall 2 comes to a halt there. When the piston rod 20 is further pushed in until the slidable rear wall 3 comes to abut on the slidable front wall 2, all the solvent liquid 11 in the rear space 5 has now been transferred into the front space 4 and mixes there with the pharmaceutical component 10 and dissolves it to form an injectable liquid 25 (FIG. 4). After the injectable liquid 25 is constituted, the piston rod 20 is further pushed in and the slidable rear wall 3 and the slidable front wall 2 together are thus moved forward so that the air in the front space 4 is expelled through the double-ended needle 18 thus to make the syringe ready for injection (FIG. 5).
In the case of a peptide hormone preparation such as growth hormone, a long-term, regular and portionwise repeated administration is needed. Such administration is conducted by a patient himself or some member of the patient's family (hereinafter referred collectively to as “patients”). The patients receive two-compartment syringes containing undissolved pharmaceutical components together with an injection device in which one of such syringes is to be loaded (see patent document 1 and FIGS. 6 and 7), and they by themselves perform the processes of mixing of the pharmaceutical components to dissolve within the two-compartment syringe and injection of the injectable liquid thus formed. FIG. 6 shows one such injection device before the dissolving process and FIG. 7 after dissolution is completed (leftward direction in both drawings represents the upward direction). Referring to FIGS. 6 and 7, mixing of the pharmaceutical components in the two-compartment syringe is performed by inserting the two-compartment syringe, held by a front casing 31′ of the injection device, into the front end of a rear casing 32′ of the injection device. This process of mixing and dissolution is just simple and can be done by patients without difficulty.
However, cases were reported at a certain frequency in which unexpected leak of liquid occurred from two-compartment syringes with an attached double-ended needle, during the mixing and dissolving processes done at patients' homes. Through various trials, the present inventors revealed that this leak of liquid was occurring in the following manner. That is, when the slidable rear wall 3 was forcefully and abruptly pushed in by patients, the forward transfer of the solvent liquid through the groove 6, as shown in FIG. 3, couldn't keep pace with it and thereby the slidable front wall 2 is pushed in beyond the groove 6 and urged in front of it, with the solvent liquid remaining between the slidable frond wall 2 and the slidable rare wall 3 (FIG. 8). Then, as the piston rod is further pressed in by patients, with part of the solvent liquid enclosed between the slidable front and rear walls 2 and 3, these walls advance together with the solvent liquid enclosed between them and, when the slidable rear wall 3 comes entirely within the range of the groove 6, the solvent liquid leaks backward through the groove 6 (FIG. 9), which is now in communication with the outside of the syringe.
When such leak of liquid as above has occurred, the pharmaceutical components are not properly mixed, and thus not only the volume of the liquid that can be ejected but also the concentration of ingredients in that liquid have been deviated from a predetermined specification, thereby rendering the two-compartment syringe improper for further use. It was also revealed that as patients became accustomed to the handling of the injection device, such rough handling of the device, on the contrary, would get more likely to take place. Thus it was difficult to eradicate occurrence of such troubles as above by simply calling their attention to the manner in which they use the device.
On the other hand, a type of device is known which utilizes a screw-based mechanism for pushing in the piston for dissolving the pharmaceutical components in the two-compartment syringe (see Patent Document 2). However, it is inconvenient and not preferable considering the diversity of patients that, in the process of dissolving, patient have to turn a screw by hand in order to push in the piston rod, because it makes handling of the device somewhat complex and thus requires more time in the dissolving process.
An injection device has been reported in which dissolving and injection of the ingredients in a two-ingredient capsule is performed using a spring (see Patent Document 3). This injection device works as follows. The ingredients are mixed when a plunger which is placed at the rear end of the loaded two-ingredient capsule is moved forwardly by the force of a spring provided in the device. Then, activation of a trigger releases the fixed capsule and allows it to be urged forwardly by the spring, causing a double-ended needle to pierce a membrane placed at the forward end of the capsule and to let the needle project from the device and eject the injectable liquid. With this device, only a single administration is possible, for the spring, once used, gets relaxed from its compressed state, and all the ingredients has been injected at once, without having provided any means for stepwise halt of the process of injection. Expulsion of air from the capsule prior to injection of the ingredient is also impossible with this device, since it, after dissolving the ingredients in the capsule, allows only a single step of operation, i.e., injection of all what is contained in the capsule.    [Patent Document 1] Japanese Patent Application Publication No. H11-267205    [Patent Document 2] Japanese Patent Publication No. H6-61361    [Patent Document 3] WO 97/48430